The Challenges of Translating Basic Research into Therapies: Resveratrol as an Example

A paper published early this year1 provided a very illuminating explanation of the difficulties of turning research results from the study of natural products into treatments. As the authors note in their introduction: “Solving problems in rodents is deceptively easy. Diabetes has been cured numerous times, exercise can be delivered in pill form, and just a few months ago, scientists were able to reverse age-related degeneration.”

The authors used the case of resveratrol, a natural molecule that has been the subject of a large amount of research for its potentially very valuable health benefits. Yet, as they explain it, the translation of this research into usable therapies for human disease is far from a simple matter.

The authors and many other scientists attended what they say is the first international conference on resveratrol and health, Resveratrol2010, which was held in September of 2010 in Helsingor, Denmark. “A clear theme of the conference, which was attended by all of the authors [of paper #1] was that multiple mechanisms are likely to contribute to the beneficial effects of resveratrol, making it difficult to agree on a specific dose, biomarker, or outcome that can define the molecule.”

The article went on to describe some of what is known about the fate of resveratrol after consumption (as part of red wine, for example). “An enterohepatic [intestine-liver] cycle of the metabolism of resveratrol has been proposed in both rats and humans. Resveratrol is quickly taken up by entero­cytes [intestinal cells] and metabolized to glucuronide and sulfate conjugates, which are secreted back to the intestine where they may be deconjugated and reabsorbed or excreted in the feces. The enterohepatic cycle reduces the concentration of the free compound reaching the body lumen. Thus, the enterohepatic cycle, along with a rapid metabolism in the liver, likely explains the low concentration of resveratrol in the bloodstream.” “It is clear that only a small fraction of the ingested resveratrol reaches the body as the parent compound. Furthermore, the amount of resveratrol ingested from dietary sources, such as red wine, juices, and so on, would very rarely exceed 5 mg, resulting in plasma levels that are either not detectable or orders of magnitude below the micromolar concentrations employed in vitro.”

The authors report that in rodent models, the doses of resveratrol can range over four orders of magnitude, from 0.1 to 1,000 mg/kg with even higher or lower doses occasionally being used. They explain that you can get different effects depending on whether a dose is high or low. “... resveratrol frequently exhibits biphasic effects. For example, resveratrol at low doses (~5 mg/kg/d) has been shown to cause weight gain in mice fed a high-fat diet, whereas at high doses (~400 mg/kg/d), there is marked weight loss. Moreover, cardioprotective effects of resveratrol that are observed at 2.5 or 5 mg/kg/d are reversed when the dose is increased to 25 or 50 mg/kg/d.” The researchers suggest that, in the face of these complications, determining a human dose from a rodent dose is a severe problem: “... there is simply no way to be confident without performing the human studies.”

The upper safe dose for resveratrol was discussed at Resveratrol2010. “Two different commercial suppliers of resveratrol, DSM Nutritional Products and Fluxome, have each reached the conclusion that 450 mg/day can be considered safe for a 60-kg individual, based on their own studies in rats and literature review (2 and www.fluxome.dk, respectively). Although the panel [at the Resveratrol2010 conference] as whole was not prepared to adopt this position without further human data, it is certainly consistent with the small number of clinical trials that have been published, several of which have included doses at or above 1 g/day without serious side effects (although the studies were short term, so long-term side effects are not known.”

Moreover, the interactions between molecules such as resveratrol and other nutrients and drugs complicate the situation further for recommending a dose for nutraceutical formulations. “Synergism of various polyphenols with resveratrol has been observed experimentally and is the specific intention of many nutraceutical formulations. In addition, resveratrol can directly interact with many drug-metabolizing enzymes and induces expression of others transcriptionally.”

Unexpected negative effects can happen as well. The authors describe how “[a] clinical trial in which multiple myeloma patients were given a proprietary formulation of resveratrol at 5 g/day was recently terminated after 5 of 24 participants developed cast nephropathy [kidney damage].” As they explain further, this sort of kidney damage is a “normal” complication of multiple myeloma, but the Wall Street Journal (December 1, 2010) reported that dehydration due to vomiting and diarrhea in the resveratrol-treated patients may have exacerbated the underlying disease. Unfortunately, as the authors note, the primary data from the trial are not available and “are not likely to be.”

Exact Mechanisms May Not Be Known

“One common concern with many drugs and supplements is that the exact mechanism of action is often unknown. From a clinical standpoint, a thorough understanding of mechanism of action is not necessarily required for widespread use. This is best exemplified in the use of general anesthetics, which are not fully understood yet are an essential component of modern medicine.” The authors note that resveratrol may affect a great many regulatory pathways. For example, “SIRT1 [thought to be activated by resveratrol] controls a number of other key regulatory factors associated with metabolism and inflammation, including p53, FoxO1, NF-kappaB, and PGC-1alpha. This complexity makes it difficult to pinpoint the events mediating beneficial effects of resveratrol or to prospectively identify potential adverse effects.”

Because exercise increases mitochondrial biogenesis through a SIRT1-dependent mechanism, it was expected that this would be observed in studies where animals were supplemented with resveratrol and, indeed, this has been observed in mice. However, “there is currently insufficient evidence to support or refute an effect in humans due to lack of research in this area. Likewise, quercetin has been demonstrated to increase markers of muscle and brain mitochondrial biogenesis, as well as endurance performance, in mice but such has not been observed in humans. Interestingly, despite the lack of effect on mitochondrial biogenesis, increased exercise performance has been reported in some but not all studies of humans taking quercetin.”

Very Few Adverse Events, But Remain Vigilant

Concerning adverse events, the researchers say, “[a]lthough there have been very few adverse events reported following resveratrol supplementation in healthy humans, there is a clear need to remain vigilant as larger populations become exposed to this, or any other nutraceutical.”

The authors suggest that a good starting point for addressing the problem of comparable efficacy between various treatments, including nutraceuticals and drugs would be to fill a “major void” by directly comparing nutraceuticals to prescription drugs. We would like to suggest that such studies are very unlikely to be done, first because pharmaceutical companies would be appalled if certain nutraceuticals were to be shown to be comparable to their far more expensive drugs in the treatment of some medical conditions. Second, nutraceutical companies are unlikely to have the many tens of millions, possibly hundreds of millions, even billions of dollars, required for such a study. Finally, no such studies would ever provide “definitive” results because it would always be possible that the choice of different doses or a longer trial or changes to a great many other variables could produce different results.

Safely Using Dietary Supplements

The one clear rule of thumb for safely taking a single dietary component or combination of dietary components that usually occur together in a food is to stick as closely as possible to the amounts ingested by people in a diet rich in those substances and that has been consumed over an extended period of time. Other than that, you should consider yourself a self-selected guinea pig, as we do when trying dietary supplements that do not fall into the class that can be correlated to dietary intake or exceed what is generally consumed in a diet rich in that substance or substances.